Fragile X syndrome (FXS)


What is fragile X syndrome?

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.
Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.
Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.


Definition: According to the National Fragile X Foundation, “Fragile X syndrome (FXS) [is] the most common cause of inherited mental impairment. This impairment can range from learning disabilities to more severe cognitive or intellectual disabilities. (Sometimes referred to as mental retardation.) FXS is the most common known cause of autism or ‘autistic-like’ behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development.”


What Causes Fragile X Syndrome?

Fragile X syndrome is caused by a defect in the FMR1 gene located on the X chromosome. The X chromosome is one of two types of sex chromosomes. The other is the Y chromosome. Women have two X chromosomes while men have one X chromosome and one Y chromosome.
The defect (mutation) on the FMR1 gene prevents the gene from properly making a protein called the fragile X mental retardation 1 protein. This protein plays a role in the functioning of the nervous system. The exact function of the protein is not fully understood. A lack or shortage of this protein causes the symptoms characteristic of fragile X syndrome.


Signs and Symptoms

Patients with fragile X syndrome present with problems in the following areas:
• Developmental
• Cognitive
• Neuropsychological
• Musculoskeletal
• Feeding
• Toilet training
• Recurrent medical conditions
Developmental features

During infancy, developmental milestones may be delayed, especially gross motor development secondary to hypotonia
• After the first year of life, delays in speech and language are notable, and fine motor skills are impaired
• As the patient matures, perseveration and echolalia may dominate speech patterns
• Expressive language ability, short-term memory, and attempts at problem solving are significantly impaired
Cognitive features

Intelligence quotient (IQ) frequently indicates mild-to-severe mental retardation (20-70)
• Females and less-affected males may have IQs that approach 80
• IQ may be higher in childhood than in adulthood because of slowing mental development and difficulties with IQ test taking rather than loss of intellect
• IQ in patients with premutations can be normal or slightly decreased
Neuropsychological features

• General and separation anxiety
• Oppositional defiant disorder
• Autisticlike behavior
• In almost all male patients, behavioral features similar to those of attention deficit-hyperactivity disorder (ADHD), including aggressive tendencies and attention deficits
• Seizure disorders (typically complex partial seizures with onset at age 6-24 months)
• As children, difficulty when routines are altered
• Features of obsessive-compulsive disorder, sensory integration disorder, or both
• Self-injurious behavior and significant tantrums


Musculoskeletal features

Pes planus
• Pectus excavatum
• Joint laxity
• Scoliosis
• Joint dislocation
Feeding difficulties

Reflux, vomiting, or both
• Rarely, failure to gain weight during infancy and childhood
• In a minority of patients, a Prader-Willi phenotype, which includes obesitydue to severe hyperphagia
Recurrent nonspecific medical problems

Recurrent sinusitis
• Otitis media
• Decreased visual acuity
The phenotype of fragile X syndrome is difficult to diagnose in prepubertal children. Most physical examination findings are notable only after onset of puberty. Physical findings are as follows:
• Growth: Childhood growth is marked by an early growth spurt, but adult height is often average or slightly below average
• Statistically significant phenotypic characteristics of young males with fragile X syndrome include the presence of a hallucal crease (a single crease between the first and second toes), sensitivity to touch, and the inability to touch the tongue to the lips
• A small subset of male patients may have obesity, poor linear growth, small hands and feet, and diffuse hyperpigmentation
• Craniofacial: Adolescent and adult patients have a long, thin face with prominent ears, facial asymmetry, a head circumference higher than the 50th percentile, and a prominent forehead and jaw
• The mouth has dental overcrowding and a high-arched palate
• Ears are typically large and may protrude
• Eyes: Strabismus is frequent; occasionally, nystagmus, astigmatism, and ptosis are present
• Hands and feet: hyperextensible finger joints, hand calluses, double-jointed thumbs, a single palmar crease, and pes planus; clubfeet may be present at birth
• Pectus excavatum and scoliosis are frequent findings
• Genitals: Macroorchidism is nearly universal in postpubertal males
• During childhood, an increased incidence of inguinal hernias is reported
• Cardiac: A heart murmur or click consistent with mitral valve prolapse is often auscultated



FMRP is found throughout the body, but in highest concentrations within the brain and testes. It appears to be primarily responsible for selectively binding to around 4% of mRNA in mammalian brains and transporting it out of the cell nucleus and to the synapses of neurons. Most of these mRNA targets have been found to be located in the dendrites of neurons, and brain tissue from humans with FXS and mouse models shows abnormal dendritic spines, which are required to increase contact with other neurons. The subsequent abnormalities in the formation and function of synapses and development of neural circuits result in impaired neuroplasticity, an integral part of memory and learning.
In addition, FMRP has been implicated in several signalling pathways that are being targeted by a number of drugs undergoing clinical trials. The group 1 metabotropic glutamate receptor (mGluR) pathway, which includes mGluR1 andmGluR5, is involved in mGluR-dependent long term depression (LTD) and long term potentiation (LTP), both of which are important mechanisms in learning. The lack of FMRP, which represses mRNA production and thereby protein synthesis, leads to exaggerated LTD. FMRP also appears to affect dopamine pathways in the prefrontal cortex which is believed to result in the attention deficit, hyperactivity and impulse control problems associated with FXS. The downregulation ofGABA pathways, which serve an inhibitory function and are involved in learning and memory, may be a factor in the anxiety symptoms which are commonly seen in FXS.



DNA testing for fragile X syndrome is recommended. Karyotyping may reveal other chromosomal anomalies, and both a standard karyotype and DNA testing are suggested when a possible diagnosis of fragile X syndrome is considered. The criterion standard diagnostic test involves molecular genetic techniques that detect the FMR1 gene. The exact number of CGG triplet repeats can be determined. Southern blot and polymerase chain reaction (PCR) are the 2 methods of genetic analysis that are currently available.
Features of Southern blot analysis are as follows:
• Provides a more accurate estimation of the number of CGG triplet repeats if a full mutation is present (with a large CGG expansion)
• Can also be used to evaluate the degree of methylation at the CGG repeat site
Features of PCR are as follows:
• Faster than Southern blot analysis
• Requires a minimal sample
• Less expensive than Southern blot analysis
• More accurately estimates the number of CGG triplet repeats if a premutation is present (with small-to-moderate increases in CGG repeats)
• PCR can be used to assess the number of AGG triplet repeats in female patients with a premutations; these AGG repeats interrupt the CGG repeats in some patients with premutations and are felt to stabilize the CGG repeats and prevent premutations in women from expanding into full mutations in their offspring; the presence and number of AGG repeats (which is directly proportional to the protection from conversion to full mutations) assist in the genetic counseling of women with premutations; therefore, greater than 2 AGG repeats is more protective than 0 or 1 AGG repeats




Due to the fact that there are no current treatments or cures for the underlying defects of FXS, it is even more critical for medical science to innovate new and efficacious pharmacological treatments as well as targeted behavioral interventions (Berry-Kravis et al., 2002).
Current trends in treating the disorder include medications for symptom-based treatments that aim to minimize the secondary characteristics associated with the disorder. If an individual is diagnosed with FXS, genetic counseling for testing family members at risk for carrying the full mutation or premutation is a critical first-step. Due to a higher prevalence of FXS in boys, the most commonly used medications are stimulants that target hyperactivity, impulsivity, and attentional problems. For co-morbid disorders with FXS, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are utilized to treat the underlying anxiety, obsessive-compulsive behaviors, and mood disorders. Following antidepressants, antipsychotics such as Risperdal and Seroquel are used to treat high rates of self-injurious, aggressive and aberrant behaviors in this population (Bailey Jr et al., 2012). Anticonvulsants are another set of pharmacological treatments used to control seizures as well as mood swings in 13%-18% of individuals suffering from FXS. Drugs targeting the mGluR5 (metabotropic glutamate receptors) that are linked with synaptic plasticity are especially beneficial for targeted symptoms of FXS. Lithium is also currently being used in clinical trials with humans, showing significant improvements in behavioral functioning, adaptive behavior, and verbal memory. Alongside pharmacological treatments, environmental influences such as home environment and parental abilities as well as behavioral interventions such as speech therapy, sensory integration, etc. all factor in together to promote adaptive functioning for individuals with FXS.
Despite the presence of many medications used to treat the secondary behavioral phenotype of FXS, medical scientists and policy makers need to work closely together in order to generate not only good science through efficacious treatments but also for increasing the available knowledge bank on molecular therapies and FXS through clinical trials of more known disorders such as ADHD and autism. Due to FXS individuals falling on a spectrum of cognitive deficits, planned educational curricula can be facilitated in order to manage better cognitive functioning for these individuals. It is important to understand the implications targeted treatments can have on not only the individuals with FXS, but also the clinicians and parents in close contact with these individuals, resulting in early diagnosing and screening matched with optimal targeted interventions.
Current pharmacological treatment centers on managing problem behaviors and psychiatric symptoms associated with FXS. However, as there has been very little research done in this specific population, the evidence to support the use of these medications in individuals with FXS is poor. While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes will lead to new therapies.
ADHD, which affects the majority of boys and 30% of girls with FXS, is frequently treated using stimulants. However, the use of stimulants in the fragile X population is associated with a greater frequency of adverse events including increased anxiety, irritability and mood lability.Anxiety, as well as mood and obsessive-compulsive symptoms, may be treated usingSSRIs, although these can also aggravate hyperactivity and cause disinhibited behavior. Atypical antipsychotics can be used to stabilise mood and control aggression, especially in those with comorbid ASD. However, monitoring is required for metabolic side effects including weight gain and diabetes, as well as movement disorders related to extrapyramidal side effects such as tardive dyskinesia. Individuals with coexisting seizure disorder may require treatment with anticonvulsants.


Management of FXS may include speech therapy, behavioral therapy, sensory integration occupational therapy, special education, or individualised educational plans, and, when necessary, treatment of physical abnormalities. Persons with fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.


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